Advancing disease-modifying therapies for Parkinson's disease: Current strategies and future directions

Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder, characterized by the accumulation of α-synuclein (α-syn) aggregates and the loss of dopaminergic neurons in the midbrain. PD affects more than 10 million individuals worldwide, but no therapy has been proven to slow down its progression, posing a significant socioeconomic burden. Developing interventions to delay or halt disease progression remains a top priority for researchers. Recently, several disease-modifying approaches have been proposed for PD treatment, such as passive immunization, small-molecule inhibitors or gene editing therapy directly targeting α-syn aggregation, mitochondrial-targeted strategies, and cell replacement therapy. Our recent research has identified FAM171A2 as a novel neuronal receptor for pathological α-syn, offering a potentially viable target for disrupting α-syn transmission that is previously not known. Further development of these strategies could offer new hope for effective treatments of PD in the near future.

Pathological α-synuclein transmission drives PD pathogenesis

PD is a progressive neurodegenerative disease, characterized by a combination of motor symptoms (e.g., bradykinesia, rigidity, and tremor) and non-motor symptoms (such as cognitive impairment, depression and anxiety, autonomic dysfunction, hyposmia, and sleep disorders). Postmortem neuropathological examinations of PD patients have identified intraneuronal inclusions, called Lewy bodies, in dopaminergic neurons, which are predominantly composed of aggregated forms of α-syn.1 Under physiological conditions, α-syn monomers are abundant in neuronal synaptic terminals, where they facilitate vesicle transport and neurotransmitter release. However, in pathological states, these naive unfolded proteins misfold and progressively aggregate into toxic oligomers, protofibrils, and mature fibrils. In addition to ultimately causing cell death, these pathological aggregates exhibit prion-like properties, capable of recruiting and converting naive ɑ-syn into pathological species, thereby driving neurodegeneration.

Previous studies revealed that cell-to-cell transmission of pathological α-syn underlies PD pathogenesis. Experimental studies demonstrated that exogenously introduced pre-formed α-syn fibrils can trigger misfolding and aggregation of endogenous α-syn monomers in both cellular and in vivo models, supporting the prion-like propagation hypothesis. This concept aligns with Braak staging observed in human neuropathology, where Lewy body pathology progresses through a temporally and spatially predictable manner and correlates with clinical manifestation of different symptoms. Additionally, increasing evidence also suggests that α-syn pathology may originate from peripheral organs, such as gut and kidney.2 Pathological α-syn from these peripheral sites can propagate to the brain and gradually spread to the midbrain. Intriguingly, the amount of α-syn pathology in substantia nigra showed significant correlation with the loss of local dopaminergic neurons in PD patients.3 Notably, autopsies of PD patients who received human fetal midbrain neuron transplants revealed Lewy body pathology in grafted neurons,4 providing additional direct evidence of α-syn transmission. Collectively, these findings underscore α-syn transmission as a key driver of neurodegeneration in PD.